Model of Transport in Renal Medullary Microvasculature

肾髓微血管运输模型

• 批准号: 6893708
• 负责人: AURELIE EDWARDS
• 金额: $ 17.05万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893708
• 关键词: electrolyte balance; hormone regulation /control mechanism; kidney circulation; lactates; mathematical model; membrane transport proteins; model design /development; nitric oxide; osmotic pressure; renal medulla; renal tubular transport; urea; water channel

DESCRIPTION (provided by applicant): The microcirculation in the renal medulla plays an essential role in the regulation of fluid and electrolyte excretion and in the long-term maintenance of arterial blood pressure. The overall goal of this research is to extend our mathematical model of the renal medullary microcirculation in order to understand the effects of specific transporters, osmolytes and hormones on medullary blood flow and its distribution. Our specific aims are as follows: Aim 1: To determine the importance of UTB urea transporters in providing a route for volume efflux that shunts blood flow from descending vasa recta (DVR) to ascending vasa recta (AVR), secondarily reducing blood flow to the inner medulla. We will incorporate new in vitro findings (including permeability and reflection coefficient measurements in UTB knockout mice) into our mathematical model in order to examine the role of water channels and urea transporters in regulating blood flow to the inner medulla. Aim 2: To examine the effects of the dependence of solute permeability on blood flow rate. Permeability of DVR to sodium and raffinose varies with perfusion rate; this dependence may be mediated by NO generation. We will investigate whether flow dependent increases in permeability reduce transmural concentration gradients and therefore water efflux from DVR, thereby enhancing blood flow to the inner medulla and decreasing concentrating ability. Aim 3: To determine whether lactate plays a significant role in the medullary microcirculation. It has been suggested that the accumulation of lactate could augment water removal from the thin descending limb and enable mathematical models to accurately predict cortico-medullary osmolality gradients. We will examine whether the presence of lactate can enhance volume efflux from DVR across transcellular pathways, thereby affecting blood flow to the papilla and axial small solute concentration gradients. Aim 4: To examine the effect of nitric oxide on overall medullary blood flow as well as on the distribution of blood flow between the inner medulla and the interbundle region of the outer medulla. We will investigate the extent to which NO generation may abrogate medullary hypoxia, and whether the production of nitric oxide by the thick ascending limb could constitute a feedback system aimed at specifically protecting the mTAL from ischemic injury, to the detriment of the inner medulla.

描述（申请人提供）：肾髓质中的微循环在调节液体和电解质排泄以及长期维持动脉血压方面发挥着重要作用。这项研究的总体目标是扩展我们的肾髓微循环数学模型，以了解特定转运蛋白、渗透剂和激素对髓质血流及其分布的影响。我们的具体目标如下： 目标 1：确定 UTB 尿素转运蛋白在提供容量流出途径方面的重要性，该途径将血流从降直肠 (DVR) 分流至升直血管 (AVR)，进而减少流向内髓质的血流。我们将把新的体外发现（包括 UTB 敲除小鼠的渗透性和反射系数测量）纳入我们的数学模型中，以检查水通道和尿素转运蛋白在调节流向内髓质的血流中的作用。 目标 2：检查溶质渗透性对血流速率的依赖性的影响。 DVR 对钠和棉子糖的渗透性随灌注速率变化；这种依赖性可能是由 NO 的产生介导的。我们将研究流量依赖的渗透性增加是否会减少跨壁浓度梯度，从而减少 DVR 的水流出，从而增强流向内髓质的血流并降低浓缩能力。 目标 3：确定乳酸在髓质微循环中是否发挥重要作用。有人认为，乳酸的积累可以增加薄降肢的水分去除，并使数学模型能够准确预测皮质髓质渗透压梯度。我们将检查乳酸的存在是否可以增强 DVR 跨细胞途径的体积流出，从而影响流向乳头的血流和轴向小溶质浓度梯度。 目标 4：检查一氧化氮对整体髓质血流以及内髓质和外髓质束间区域之间血流分布的影响。我们将研究一氧化氮的产生在多大程度上可以消除髓质缺氧，以及厚升肢产生的一氧化氮是否可以构成一个反馈系统，旨在专门保护 mTAL 免受缺血性损伤，从而损害内髓质。